Targeting BMP signalling in cardiovascular disease and anaemia

Abstract

Bone morphogenetic proteins (BMPs) and their receptors, known to be essential regulators of embryonic patterning and organogenesis, are also critical for the regulation of cardiovascular structure and function. In addition to their contributions to syndromic disorders including heart and vascular development, BMP signalling is increasingly recognized for its influence on endocrine-like functions in postnatal cardiovascular and metabolic homeostasis. In this Review, we discuss several critical and novel aspects of BMP signalling in cardiovascular health and disease, which highlight the cell-specific and context-specific nature of BMP signalling. Based on advancing knowledge of the physiological roles and regulation of BMP signalling, we indicate opportunities for therapeutic intervention in a range of cardiovascular conditions including atherosclerosis and pulmonary arterial hypertension, as well as for anaemia of inflammation. Depending on the context and the repertoire of ligands and receptors involved in specific disease processes, the selective inhibition or enhancement of signalling via particular BMP ligands (such as in atherosclerosis and pulmonary arterial hypertension, respectively) might be beneficial. The development of selective small molecule antagonists of BMP receptors, and the identification of ligands selective for BMP receptor complexes expressed in the vasculature provide the most immediate opportunities for new therapies.

Figure 1. The repertoire of receptor complexes and ligands involved in cardiovascular and related metabolic responses to BMP signalling

A variety of BMP ligands (BMP6, BMP9, and BMP10) are present in the circulation at biologically active concentrations. Endothelial cells (EC), vascular smooth muscle cells (SMC), and adventitial myofibroblast cells (AC) express receptors, co-receptors, and antagonists in a tissue-specific manner to permit complementarity and precise regulation of signalling. Congenital vascular syndromes are shown in red to depict the loss-of-function of several of these signalling molecules, resulting in human hereditary telangiectasia (HHT) syndromes HHT1, HHT2, HHT5, and heritable pulmonary arterial hypertension (HPAH). Positive regulatory effects downstream of BMP signalling are depicted by green arrows, whereas negative effects are depicted with red arrows. Hepatocytes respond to BMP6 signaling to express hepcidin, which subsequently downregulates expression of ferroportin (FPN) to increase the retention of Fe⁺² in macrophages (MΦ) and duodenal enterocytes, consequently enhancing macrophage activation and reducing serum iron. This activity contributes to iron-deficiency anaemia associated with chronic inflammatory states, and potentiates the activity of macrophages and foam cells in atherosclerosis. While BMP9 signalling appears to be protective in endothelial cells, signalling by BMP2, BMP4, and BMP6 appear to be osteogenic and pro-atherogenic in SMC and EC, acting downstream of atherogenic stimuli including oxidized LDL (oxLDL) via the induction of reactive oxygen species to promote atherosclerosis and vascular calcification. Abbreviations:

Figure 2. Potential approaches to target and enhance signalling or expression of BMPRII

BMPRII cell surface expression can be increased by endothelial gene therapy targeted to the pulmonary circulation. This increase in BMPRII can be achieved using small molecules that increase translational read through of BMPRII mutations encoding premature termination codons, and chemical chaperones that increase trafficking of BMPRII misfolded mutations that are held up within the endoplasmic reticulum. In addition, BMPRII signalling can be restored by ligands (BMP9 and BMP10) that target the BMPRII/ALK1 receptor complex on endothelial cells, and agents that enhance downstream SMAD phosphorylation, such as tacrolimus, sildenafil, and prostanoids. Finally, inhibition of BMPRII turnover by the lysosome, using agents such as hydroxychloroquine, can enhance cell surface expression of BMPRII protein. Abbreviations: